First primate born using frozen testicle technique

ON JANUARY 15, 2018, doctors at Oregon National Primate Research Center performed a routine ultrasound on a rhesus macaque. Everything looked normal; the baby's head floated to one side, its developing spine trailing away like a zipper.

However, this baby was anything but common: The infant was soon to be the first primate born from a procedure using cryopreserved testicular tissue taken from a prepubescent monkey. Researchers had grafted the tissue under its host's skin to mature and then, using in vitro fertilisation, had created the baby monkey, which was dubbed Grady after her graft-derived origins.

Described today in the journal Science, the achievement offers hope for men who face infertility as a side effect of chemotherapy and radiation treatments for childhood cancer. Adult men can choose to freeze their sperm before starting treatments that have the potential to damage their gonads. But that's not the case for boys, who have not yet begun producing sperm.

Grady clutches a towel, her eyes open wide, at two weeks old.
OHSU

With the survival rate of childhood cancers now higher than 80 percent, the need for such fertility assistance is growing. Clinics around the world are already freezing testicular tissue for prepubescent boys, and at least a thousand patients have opted in, according to estimates by study author Kyle Orwig, senior researcher at Magee-Womens Research Institute of the University of Pittsburgh Medical Center.

Though there are a few potential methods that make use of this frozen tissue in the research pipeline, none are yet available to patients. Now, Grady's birth hints the situation may soon change.

“It is a milestone for further clinical application,” says Christine Wyns, head of the gynecology and andrology department at the Cliniques Universitaires Saint-Luc, Belgium, who was not involved in the study.

Menagerie of model animals

First described in 2002, studies testing variations on this method have been piling up over the years, including work with mice, pigs, goats, rabbits, hamsters, dogs, cats, horses, cattle, and other monkeys. For this menagerie, researchers collected immature testicular tissue and then grafted it under the skin of mice to allow it to mature and produce sperm.

The birth of live babies, however, has been less common. And just a few studies have ever re-implanted the testicular tissue back into the same host animal to mature.

The vast majority of these studies also relied on tissues that had never been frozen for preservation. Known as cryopreservation, this step will be vital to protect the viability of tissues from human boys for future fertility. Even more important: No scientists had previously used cryopreserved tissue re-implanted into its host to seed the birth of baby monkeys, animals that sit close to humans on the evolutionary tree. This version of the method is the most likely to eventually be used in humans, so that's what the new research tackled.

The team removed one testis from each of the five prepubescent monkeys in the study, cut it into small pieces, and cryopreserved it for five to seven months as the monkeys approached puberty. The scientists later removed the second testicle, chopping it into pieces. They then grafted the tiny lumps from both fresh and previously frozen testicle tissues back under the monkeys' skin.

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“Here, the objective is not to hook it up to the normal plumbing or restore normal spermatogenesis,” Orwig says. Instead, by returning the tissue to the host, it can mature using the body's natural hormones. Between eight and 12 months later, the team successfully removed the 39 grafts—all of which had developed enough to produce sperm. They then recovered sperm from the majority of the removed grafts.

“That’s where a lot of studies stop. They just say, Okay, we’ve got sperm. Ta-da,” Orwig says. “But you can imagine just because you have sperm, doesn’t mean they’re able to fertilise or make a baby.”

So researchers at the Oregon primate center used the resulting sperm to fertilise monkey eggs and implanted 11 developing embryos into six adult monkeys. One birthed a healthy baby girl: Grady.

Future fertility

While the results have generated lots of excitement, there is also caution about when humans should enter the equation. The method wouldn't work for everyone. Children with cancers that may form malignant cells in their testes, for example, shouldn't have that material grafted back into their body, so other methods are being developed to tackle this issue.

Also there's still some lingering concern about later effects to the child born from this procedure. In the months following her momentous birth, Grady behaved and grew normally, but Wyns stresses the need to fully evaluate the sperm's chromosomes to ensure the method doesn't unwittingly meddle with genes or their expression—a step that Oriwg notes is challenging to study but agrees would be worth pursuing in follow-up studies.

Then there's the monkeys' lack of testicles. For a variety of reasons, the animals were castrated in all previous studies, including this latest work. But potential human patients would likely still have their testicles intact, says Susan Taymans, a program director at the fertility and infertility branch of Eunice Kennedy Shriver National Institute of Child Health and Human Development, which helped fund the work. Orwig and his colleagues acknowledge the need for more experiments in monkeys to test how this might influence the outcomes.

“Even though those are the things we need to continue to do,” Orwig says, “I do believe this is a technique that is ready to go to the clinic today.”

Now may indeed be the time for clinical trials, agree Nina Neuhaus and Stefan Schlatt of the Centre of Reproductive Medicine and Andrology, Germany, in a News and Views article accompanying the study. Because IVF is routine in humans, they note, birth rates will likely be higher than in the monkey trials.

“We owe it to those patients to bring things to the clinic—as long as we’ve demonstrated the appropriate safety and feasibility—to bring things to the clinic as quickly as we can,” Orwig says, noting this is his personal perspective and not all in the field may agree.
In the meantime, he stresses the need for counseling young patients and their families on the impacts of looming cancer treatments on their future fertility.

By not doing so, he says, “we've robbed them of the full potential of life that they expected to have...I believe in my soul that it’s an important thing to do, and cancer patients, survivors, and their families really want it.”

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